Heterocyclic compounds

ABSTRACT

1-(3&#39;&#39;,4&#39;&#39;-METHYLENEDIOXYBENZYL)-PIPERAZINES SUBSTITUTED IN 4-POSITION BY (1) PYRIMIDIN-4-YL, PYRAZINYL, S-TRIAZINYL, OR QUINAZOLINYL UNSUBSTITUTED OR SUBSTITUTED BY ONE OR TWO ALKYL, ALKOXY OR AMINO GROUPS, OR (2) PYRIMIDIN-2-YL MONOSUBSTITUTED BY HALOGEN, CARBOXY, CARBALKOXY, OR CARLAKOXYMETHOXY, OR DISUBSTITUTED BY ALKOXY AND CARBOXY OR CARBALKOXY. THESE COMPOUNDS POSSES BRONCHODILATING AND PERIPHERAL VASODILATING PROPERTIES.

United States Patent 015cc 3,585,193 HETEROCYCLIC COMPOUNDS GilbertRegnier, Sceaux, Roger Canevari, LHay les Roses, and Michel Lauhie,Vaucresson, France, assignors to Societe en nom collectif Science Unionet Cie, Societe Francaise de Recherche Medicale, Suresnes, France NDrawing. Filed Nov. 8, 1968, Ser. No. 774,478 Claims priority,application Great Britain, Nov. 15, 1967, 57,999/67 Int. Cl. C0711 99/04US. Cl. 260256.4 4 Claims ABSTRACT OF THE DISCLOSURE The presentinvention provides new heterocyclic compounds of the general formula-OH2N N-Het in which Het represents a pyrimidinyl radical attached inthe 4- position, or a prazinyl, s-triazinyl, or quinazolinyl radicalwhich may be unsubstituted or substituted by one two lower alkylradicals containing 1 to 4 carbon atoms, by lower alkoxy radicalscontaining 1 to 4 carbon atoms, or by an amino group, or a pyrimidinylradical attached in the 2-position which is mono-substituted by ahalogen atom or by a carboxy, carbalkoxy or carbalkoxymethoxy group, ordisubstituted by an alkoxy radical and a carboxy or carbalkoxy radical,wherein the alkoxy have from 1 to 4 carbon atoms inclusive.

The new compounds of this invention are obtained by condensing ahalogenated derivative of the general formula HetZ II) where Zrepresents a chlorine or bromine atom and Het has the meaning givenabove with 1-(3,4-methylenedioxybenzy1)-piperazine of the formula Thecondensation is carried out in a polar solvent such, for example, as ahigh-boiling alcohol, for example butanol or pentanol, or in an aromaticamide such, for example, as dimehtylformamide, in a non-polar sol ventsuch, for example, as an aromatic hydrocarbon, for example benzene,toluene or xylene. The condensation is advantageously carried out at atemperature ranging from 80 to 140 C. in the presence of an acceptor forthe hydrohalic acid formed during the reaction. The latter may be analkali or alkaline earth metal salt of carbonic acid such, for example,as the bicarbonate or carbonate of sodium or potassium, or calciumcarbonate, or a tertiary organic base, for example, dimethylaniline,pyridine or 3,585,193 Patented June 15, 1971 triethylamine. If desired,these salts or tertiary bases may be replaced by an excess of themonosubstituted piperazine.

The new heterocyclic compounds obtained in this manner are weak basesand can be converted into acid addition salts which are likewiseincluded in this invention. These acid addition salts are obtained byreacting the new derivatives with acids in suitable solvents, forexample in water or water-miscible alcohols. As acids capable of formingsuch acid addition salts there may be mentioned mineral acids such, forexample, as hydrochloric, hydrobromic, methanesulphonic, sulphuric andphosphoric acids, and organic acids such as acetic, propionic, maleic,fumaric, tartaric, citric, oxalic, benzoic acid and the like.

If desired or required, the new compounds may be purified by physicaloperations such as distillation, crystallization or chromatography, orby chemical operations such as decomposition of the acid addition saltsby reaction with alkaline agents.

The compounds of the invention possess interesting pharmacological andtherapeutic properties and may be used especially as peripheralvasodilators and bronchodilators.

The acute toxicity was determined in mice and it was found that the DLvaries from 50 to 1500 mg./'kg. LP. and from 1200 to 3000 mg./kg. P.O.according to the compound tested.

An intravenous perfusion of the new compounds at a level of 5 mg./kg. inthe rabbit increases the blood flow of the paw from 20 to 225%,demonstrating an important vasodilator activity.

The bronchodilator activity was demonstrated by the method of Konzettand Rossler [Arch. Exptl. Pathol. U. Pharmak. 195, 71 (1940)]. It wasfound that the new compounds inhibit the bronchospasm in the guinea-pigprovoked by histamine, serotonine or acetylcholine. The doses from 1 to5 mg./kg. administered intravenously inhibit these spasms from 30 to100%.

These properties enable the use of the new compounds in therapy, andespecially in the treatment of peripheral circulatory disorders such,for example, as arteritis or phlebitis, chronic or acute respiratoryinsufficiency, and particularly bronchial asthma.

The doses used may vary from 10 to 200 mg., and the dosage regimen maybe 2 to 4 times per day.

The compounds can be administered per oral, rectal or parenteral route,and the active principle may be mixed or associated with the usualpharmaceutical carriers such as: distilled water, starch, talc, lactose,ethyl cellulose, cocoa butter, according to the desired pharmaceuticalform, which can be: tablet, drage, capsule suppository, injectable ordrinkable solution.

The pharmaceutical preparations containing a compound of the generalFormula I, or one of its salts in admixture or conjunction with apharmaceutically suitable carrier are also a part of this invention.

The following examples illustrate the manufacture of the new compounds.The melting points were determined on a Kofler heater under amicroscope, unless otherwise indicated.

EXAMPLE 1 1- 5 -chloro-pyrimidin-2-yl) -4- (3 ,4' methylendioxyb enzyl-pip er azine 28 grams of potassium carbonate are added to a solution of21 g. of 1 (3',4-methylenedioxybenzyl)-piperazine and 14.9 g. of2,5-dichloropyrimidine in 150 cc. of dimethylformamide (DMF) and themixture is heated for 8 hours at C. After this time the salt formed isfiltered 01f, the DMF is distilled 01f under reduced pressure and thehot residue is poured into 100 cc. of boiling water. The whole isvigorously agitated while being cooled, whereupon the oil crystallizes;it is suctioned off and recrystallized from ethanol, to yield 25 g. ofcream colored crystals melting at 99-101 C.

The following derivatives may be prepared as described above, using theappropriate starting materials:

(a) 1-(4'-carbethoxy-methoxy-pyrimidin 2' yl) 4- (3,4methylenedioxybenzyl)-piperazine, starting from2-chloro-4-carbethoxy-methoxy-pyrimidine. Its dihydrochloride melts at195-200 C.

In the same manner other 4' carbalkoxy-methoxypyrimidin-2'-yl compoundsare prepared, starting only from the appropriate starting material,wherein alkoxy has 1 to 4 carbon atoms inclusive, for example, thecorresponding carbomethoxy, carbopropoxy, carboisopropoxy andcarbobutoxy compounds.

(b) 1- 5 -carbethoxy-pyrimidin-2'-yl -4-( 3",4"-methylenedioxybenzyl)-piperazine, starting from 2 chloro-S-carbethoxy-pyrimidine. The free base melts at 104 C.

In the same manner other 5-carbalkoxy-pyrimidin-2'- yl compounds areprepared, starting only from the appropriate starting material, whereinalkoxy has 1 to 4 carbon atoms inclusive, for example, the correspondingcarbomethoxy, carbopropoxy, carboisopropoxy and carbobutoxy compounds.

(c) 1 (4 ethoxy-S-carbethoxy-pyrimidin-2-yl)-4-(3,4"-methylenedioxybenzyl)piperazine, starting from 2-chloro-4-ethoxy-5-carbethoxy-pyrimidine. Its hydrochloride melts at 260C.

In the same manner other 4-alkoxy-5-carbethoxy-pyrimidin-2-yl compoundsare prepared starting only from the appropriate starting material,wherein alkoxy has 1 to 4 carbon atoms inclusive, for example thecorresponding methoxy, propoxy, isopropoxy and butoxy compounds.

(d) 1-(4'-ethoxy-5-carboxy-pyrimidin-2'-y1)-4-(3 ",4"-methylenedioxybenzyl)-piperazine, starting from 2-chloro-4-ethoxy-S-carboxy-pyrimidine. Its hydrochloride melts at 196-200 C.

In the same manner other 4'-alkoxy-5'-carboxy-pyrimidin-2-yl compoundsare prepared, starting only from the appropriate starting material,wherein alkoxy has 1 to 4 carbon atoms inclusive, for example, thecorresponding methoxy, propoxy, isopropoxy and butoxy compounds.

(e) 1-(5-carboxy pyrimidin2'-yl)-4-(3,4-methylenedioxybenzyl)-piperazine, starting from2-chloro-5- carboxy-pyrimidine. The free base melts at 234 C.

EXAMPLE 2 1-(pyrimidin-4-yl)-4- 3,4"-methylenedioxybenzyl)- piperazineThis compound is obtained by working according to the method given inExample 1 in toluene under reflux in the presence of potassium carbonateand starting from 4-chloropyrimidine. The corresponding dihydrochloridemelts at 192-198 C. with decomposition.

In the same manner as described in this example the following compoundwas obtained:

1-(2' amino pyrimidin-4'-yl)-4-(3",4"-methylene dioxybenzyl)-piperazine,starting from 2-amino-4-chl0ropyrimidine. The free base melts at 171 C.

EXAMPLE 3l-(4',6'-dimethoxy-s-triazin-2'-yl)-4-(3",4-methylenedioxybenzyl-piperazine This compound is obtained by Working according to the methodgiven in Example 1 in benzene under reflux in the presence of potassiumcarbonate and starting from 2-chloro-4,6-dimethoxy-s-triazine. The freebase melts on a Kofler heater at 102 C. The corresponding hydrochloridemelts at 250 C. with decomposition.

1- (quinazolin-4'-yl)-4-(3",4"-methylenedioxybenzyl)- piperazine Thiscompound is obtained by working according to the method given in Example1 in dimethylforrnamide in the presence of potassium carbonate andstarting from 4- chloroquinazoline. The corresponding dihydrochloridemelts as 230233 C.

The following compounds were obtained as described in this example:

(a) l-(quinazolin 2 yl)-4-(3,4-methylenedioxybenzyl)-piperazine,starting from 2-chloro quinazoline. The free base melts at 141 C.

(b) 1-(2-methyl-quinazolin 4yl)-4-(3",4"-methylenedioxybenzyl)-piperazine, starting from 2-methyl-4-chloro-quinazoline. The dihydrochloride melts at 210- 218 C.

EXAMPLE 5 1- pyrazin-3 '-yl -4- 3 ',4"-methylenedioxybenzyl piperazineThis compound is obtained by working according to the method given inExample 1 in dimethylformamide in the presence of potassium carbonateand starting from 3- chloropyrazine. The dihydrochloride melts at228-234 C. (capillary).

The following compounds were also obtained by the method described inthis example:

(a) 1-(2,5'-dimethyl-pyrazin 3'yl)-4-(3",4-methylenedioxybenzyl)-piperazine, starting from2,5-dimethyl- 3-chloropyrazine. The dihydrochloride melts at 273- 275 C.

(b) l-(5'-methyl-pyrazin 3' yl)-4-(3,4",methylenedioxybenzyl)-piperazine, starting from 3-chloro-5-methyl-pyrazine. The dihydrochloride melts at 254-255 C (c)1-(2-amino-pyrazin 3 yl)-4-(3,4-methylenedioxybenzyl)-piperazine,starting from 2-amino-3-chloropyrazine. The dihydrochloride melts at225228 C.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, compositions, and methods ofthe present invention without departing from the spirit or scopethereof, and it is therefore to be understood that the invention is tobe limited only by the scope of the appended claims.

What we claim is:

1. A compound selected from the group consisting of (A) heterocycliccompounds of the Formula I CH2N N-Het wherein Het is selected from thegroup consisting of:

quinazolinyl optionally substituted by a substituent selected from thegroup consisting of lower-alkyl of up 6 to 4 carbon atoms inclusive,lower-alkoxy of up to References Cited incltusge 33 39 i f UNITED STATESPATENTS P glca y amp a e a sa S 3,119,826 1/1964 Regnier et a1. 260-268organic and mineral acids. 2. l-(quinazolin 4'yl)-4-(3",4"-methylenedioxy- 5 ALEX M AZEL Primary Examinerbenzyl)-piperazine.

3 l (quinazoline Y1)-4-(3"a4mmethylenedioxy R. GALLAGHER, AsslstantExamlner benzy1)-p1peraz1ne. US Cl.

4. 1-(2'-methyl-quinazo1in-4-yl) 4(3,4"-methylenedioxybenzyl)-pipe1azine 10 260-2495, 249.8, 256.5, 268;424-200, 249, 250, 251

